EP0219912B1

EP0219912B1 - The use of nitrofurantoin for the treatment and prophylaxis of gastrointestinal disorders

Info

Publication number: EP0219912B1
Application number: EP86201789A
Authority: EP
Inventors: William Gerald Kraft; Donna Rene Morgan
Original assignee: Norwich Eaton Pharmaceuticals Inc
Current assignee: Warner Chilcott Pharmaceuticals Inc
Priority date: 1985-10-24
Filing date: 1986-10-15
Publication date: 1992-07-15
Anticipated expiration: 2006-10-15
Also published as: EP0219912A2; JP2669818B2; DE3686019T2; EP0219912A3; US4959384A; DE3686019D1; JPS62161726A; PH21421A; IE59739B1; IE862800L

Description

TECHNICAL FIELD

The present invention relates to the use of nitrofurantoin for the manufacture of a medicament for the treatment and prophylaxis of infectious gastrointestinal disorders in humans and other animals as defined below.

BACKGROUND OF THE INVENTION

Factors adversely affecting the function of the gastrointestinal system in humans are exceedingly varied in their nature. Such disorders may arise in the upper or lower gastrointestinal tracts or both. There is a broad range of causes of gastrointestinal disorders, including genetic, physiological, environmental, and psychogenic factors. Accordingly, the diagnosis and management of these disorders can be exceptionally difficult. A detailed discussion of gastrointestinal tract functions, disorders, causes, and treatments can be found in Spiro, Clinical Gastroenterology (3d. edition 1983).
Among the chronic disorders of the upper gastrointestinal tract are those which fall under the general categories of gastritis and peptic ulcer disease. (The upper gastrointestinal tract as used herein is defined as including the esophagus, the stomach, the duodenum and the jejunum.) Gastritis is, by definition, typified by an inflammation of the stomach mucosa. In practice, though, the disorder is manifested by a broad range of poorly-defined, and heretofore inadequately treated, symptoms such as indigestion, "heart burn", dyspepsia and excessive eructation. A general discussion of gastritis appears in B. J. Marshall and J. R. Warren, "Unidentified Curved Bacilli in the Stomach of Patients with Gastritis and Peptic Ulceration", The Lancet, (1984), pp. 1311-1315, and in R. Greenlaw, et al., "Gastroduodenitis, A Broader Concept of Peptic Ulcer Disease", Digestive Diseases and Sciences, Vol. 25 (1980), pp. 660-672.
Peptic ulcers are lesions of the gastrointestinal tract lining, characterized by loss of tissue due to the action of digestive acids and pepsin. It has been generally held that peptic ulcers are caused either by gastric hypersecretion, or (more often) by decreased resistance of the gastric lining to digestive acids and pepsin. The medical literature is replete with methods for treating ulcers, including modification of the diet, surgical removal of the lesions, and the use of drugs. Such drugs include; antacids, which serve to counteract excess gastric secretions; anticholinergics, which reduce acid secretion; H₂ antagonists, which also block the release of gastric acids; prostaglandins, which increase the resistance of the gastric lining to digestive fluids, and may also inhibit acid secretion; prokinetic agents, which enhance gastrointestinal tract motility; and compositions which form protective barriers over gastric lesions. Prescription and non-prescription drug therapies are generally described in Garnet, "Antacid Products", Handbook of Non-prescription Drugs, 7th edition (1982), Chapter 3.
Regardless of the particular drug composition used in treating gastrointestinal disorders, such as gastritis or peptic ulcer disease, the treatment is often imprecise and incomplete. Actual "cures", i.e., successful treatment resulting in total remission of disease, are very often not effected. See A. J. McLean, et al., "Cyto-protective Agents and Ulcer Relapse", 142 The Medical Journal of Australia, Special Supplement S25-S28 (1985). Furthermore, many conventional treatments may render subject hypochlorhydric (i.e., with low levels of hydrochloric acid in the stomach) which may predispose them to other disorders, e.g., gastrointestinal infection, halitosis, and gastric carcinomas.
Nitrofurantoin is a well-known antibacterial compound and has been used extensively as an active ingredient in antibacterial pharmaceutical compositions. See, for example, Mintzer, S., E.R. Kadison, W.H. Shlaes & O. Felsenfeld, "Treatment of Urinary Tract Infections with a New Antibacterial Nitrofuran", Antibiotics & Chemotherapy, Vol. 3, No. 2 (February, 1953), pp. 151-157; Richards, W.A., E. Riss, E.H. Kass & M. Finland, "Nitrofurantoin - Clinical and Laboratory Studies In Urinary Tract Infections", Archives of Internal Medicine, Vol. 96 (1955), pp. 437-450; Eudy, W.W., "Correlations Between In Vitro Sensitivity Testing and Therapeutic Response in Urinary Tract Infections", Urology, Vol. II, No. 5 (November, 1973), pp. 519-587; Bush, I.M., W.I. Metzger, I. Garlovsky, R.B. Bush, R.J. Ablin & N. Sadoughi, "Urinary Tract Infection - Antibacterial Susceptibility Patterns", Urology, Vol. III, No. 6 (June, 1974), pp. 697-700; Dickey, L., "A Comparison of the In Vitro Effectiveness of Nitrofurantoin and Five Antibiotics Against Bacteria from Urinary Tract Infections", American Journal of Medical Technology, (September-October, 1961) , pp. 273-279; Karmali, M.A., S. DeGrandis & P.C. Fleming, "Antimicrobial Susceptibility of Campylobacter jejuni with Special Reference to Resistance Patterns of Canadian Isolates", Antimicrobial Agents and Chemotherapy, Vol. 19, No. 4 (1981), pp. 593-597.
Antimicrobial Agents and Chemotherapy, Vol.27 (1985) pp.55-59 describes the in vitro activity of some drugs against Campylobacter organisms. Antimicrobial Agents and Chemotherapy, Vol.26 (1984) pp.498-500 describes the comparative antibacterial activity of antimicrobial agents selected from nitrothiazole, nitroimidazole and nitrofuran derivatives.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide the manufacture of a medicament for treating infectious gastrointestinal disorders of the upper gastrointestinal tract of a human or lower animal which are caused or mediated by Campylobacter pyloridis.
It is also an object of the present invention to provide the manufacture of a medicament for preventing recurrence of infectious gastrointestinal disorders of the upper gastrointestinal tract of a human or lower animal which are caused or mediated by Campylobacter pyloridis.
The treatment of a human or lower animal subject having an infectious gastrointestinal disorder or for prevention of recurrence of such disorder by administering to such subject a safe and effective amount of nitrofurantoin is described below.

DETAILED DESCRIPTION OF INVENTION

Specific compositions to be prepared according to the present invention must, accordingly, be pharmaceutically acceptable. As used herein, a "pharmaceutically-acceptable" component is one which is suitable for use with humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio. Further, as used herein, the term "safe and effective amount" refers to the quantity of a component which is sufficient to yield a desired therapeutic response without undue adverse effects (such as toxicity, irritation, or allergic response) commensurate with a reasonable benefit/risk ratio when used in the manner of this invention. The specific "safe and effective amount" will, obviously, vary with such factors as the particular condition that is being treated, the physical condition of the patient, the nature of concurrent therapy (if any), and the specific formulations employed in the present invention. The treatment and prophylaxis of a human or lower animal subject having an infectious gastrointestinal disorder and the administration of a safe and effective amount of nitrofurantoin to said subject are described herein.
As used herein, "infectious gastrointestinal disorder" emcompasses any disease or other disorder of the upper gastrointestinal tract of a human or lower animal which is caused or mediated by Campylobacter pyloridis. Such infectious gastrointestinal disorders include, for example disorders not manifested by presence of ulcerations in the gastric mucosa (herein "non-ulcerative gastrointestinal disorder"), including chronic or atrophic gastritis, non-ulcer dyspepsia, esophageal reflux disease and gastric motility disorders; and "peptic ulcer disease", i.e., Campylobacter pyloridis-mediated gastric, duodenal, and jejunal ulcers.
As used herein, "administering" refers to any method which, in sound medical practice, delivers the compounds or compositions used in this invention to the subject to be treated in such a manner so as to be effective in the treatment or prophylaxis of the infectious gastrointestinal disorder. Preferably, the nitrofurantoin is administered orally.
As used herein, "prophylaxis" refers to the prevention of the occurrence of infectious gastrointestinal disorders in human or lower animals. While the methods of the present invention could be used for the prevention of such disorders in any human or lower animals, it is preferred to use the prophylactic treatment of nitrofurantoin in subjects which have a history of recurring infectious gastrointestinal disorders.
As used herein, "nitrofurantoin" is the compound which has the chemical structure:

or its pharmaceutically acceptable salts, hydrates, or complexes. As used herein, nitrofurantoin "complexes" refer to chemical complexes of nitrofurantoin with other chemical constituents which result in entities which retain at least a substantial portion of the antimicrobial activity of nitrofurantoin. Examples of such complexes include nitrofurantoin-phthaloyl glycine and nitrofurantoin-phthaloyl aminocaproic acid.
Nitrofurantoin has been found to have a high degree of antimicrobial activity against Campylobacter pyloridis. This activity of nitrofurantoin is surprising in light of the finding that related antibacterial substances have substantially less activity than nitrofurantoin against Campylobacter pyloridis. Also, other antibacterial substances known to be useful in combatting the same types of bacterial infections for which nitrofurantoin is commonly used and other antibacterial substances commonly used for treatment of gastrointestinal disorders have substantially less activity than nitrofurantoin against Campylobacter pyloridis.
The use of the present invention involves the preparation of a medicament containing a safe and effective amount of nitrofurantoin to a human or lower animal for the treatment or prophylaxis of infectious gastrointestinal disorders. The preferred daily dosage of nitrofurantoin is from 1 mg to 600 mg of nitrofurantoin per day, especially preferred is from 10 mg to 400 mg of nitrofurantoin per day, more preferred still is from 20 mg to 200 mg of nitrofurantoin per day.
The administration of the above daily doses of nitrofurantoin is continued until the disorder has been eradicated from the human or lower animal. It is preferred that the daily dosages be administered to the human or lower animal for a period of from 1 day to 200 days, more preferably from 3 days to 60 days, more preferably still from 7 days to 30 days.
The prophylaxis of infectious gastrointestinal disorders preferably involves the administration of the above doses of nitrofurantoin on a daily or less frequent basis in order to prevent recurrence of the disorder in the human or lower animal. It is preferred that the dosages be administered to the human or lower animal daily from 1 day to 200 days, more preferably from 7 days to 150 days, more preferably still from 30 days to 100 days. It is also preferred that the dosages be administered to the human or lower animal every 2 or 3 days for from 7 days to 400 days, more preferably from 30 days to 300 days, more preferably still from 60 days to 200 days. It is also preferred that the dosages be administered to the human or lower animal about weekly for a period of from 14 days to 800 days, more preferably from 30 days to 600 days, more preferably still from 60 days to 400 days.

Optional Components and Methods:

The methods of this invention may incorporate optional steps modifying the present specific use. Such optional steps may also utilize optional components or compositions. Such optional components or compositions must not, however, adversely affect the therapeutic activity of the nitrofurantoin.
Before any treatment a diagnostic step for the detection of a Campylobacter pyloridis infection in the upper gastrointestinal tract of the human or lower animal subject is to be carried out by taking a biopsy of the affected tissue and identifying the presence of the above organism by conventional histological examination, e.g. fixing the tissue in paraffin for Hematoxylin and Eosin stain and in plastic for Warthin Starry Silver stain. (See Steer, H.W. & D.G. Colin-Jones, "Mucosal changes in gastric ulceration and their response to carbenoxolone sodium", Gut, Vol. 16 (1975), pp. 590-597; McNulty, C.A.M. & D.M. Watson, "Spiral Bacteria of the Gastric Antrum", The Lancet, Vol. 1, No. 8385 (May, 1984), pp. 1068-1069; Jones, D.M., A.M. Lessells & J. Eldridge, "Campylobacter like organisms on the gastric mucosa: culture, histological, and serolopical studies", Journal of Clinical Pathology, "Vol. 37 (1984), pp. 1002-1006; Rollason, T.P., J. Stone & J.M. Rhodes, "Spiral organisms in endoscopic biopsies of the human stomach", Journal of Clinical Pathology, Vol. 37 (1984), pp. 23-26.) This diagnostic step is preferably performed prior to the step of administering nitrofurantoin. Also preferably, the diagnostic step is repeated during the step of administering the nitrofurantoin, and the step of administering the nitrofurantoin is terminated after the diagnostic step yields a negative result, unless prophylactic treatment of the human or lower animal is desired.
The following examples illustrate the present use.

EXAMPLE I

A human subject, suffering from atrophic gastritis, is treated by a medicament as prepared according to the present invention. Specifically, the subject is endoscoped and a biopsy taken of the gastric mucosa of the subject. Analysis of the biopsy sample shows inflammation of the mucosa, and depletion of the protective mucous layer. Histological examination of the sample also reveals the presence of Campylobacter pyloridis. The subject is then treated, according to the present invention, by administering a composition containing nitrofurantoin, sold by Norwich Eaton Pharmaceuticals, Inc. under the name "Furadantin". The composition, in oral suspension form, is administered 4 times daily in equal doses of 100 milligrams (for a total of approximately 400 milligrams of nitrofurantoin administered per day) for 14 days. Thereafter, the subject is endoscoped and biopsied again, finding essentially normal, healed gastric mucosa. Histological examination of the gastric material sample does not reveal any bacterial infection. The subject remains asymptomatic, and another biopsy performed five months later reveals normal gastric mucosa.

Claims

The use of nitrufurantoin for the manufacture of a medicament for the treatment of a human or lower animal subject having an infectious gastrointestinal disorder of the upper gastrointestinal tract, selected from non-ulcerative gastrointestinal disorder and peptic ulcer disease, which is caused or mediated by Campylobacter pyloridis.
The use of Claim 1 wherein said medicament is for oral administration for the treatment of an infectious gastrointestinal disorder of the esophagus, stomach or duodenum, which is caused or mediated by Campylobacter pyloridis.
The use of claim 1 or 2 wherein said manufacture comprises the preparation of a medicament containing from 1 to 600 mg of nitrofurantoin in one or more unitary doses.
The use of claim 3 wherein said dose comprises from 1 to 200 mg of nitrofurantoin.
The use of any Claims 1 through 4 wherein said infectious gastrointestinal disorder is gastritis.
The use of any Claims 1 through 4 wherein said infectious gastrointestinal disorder is peptic ulcer disease.
The use of nitrofurantoin for the manufacture of a medicament for the prophylactic treatment of a human or lower animal subject for prevention of infectious gastrointestinal disorders of the upper gastrointestinal tract, selected from non-ulcerative gastrointestinal disorder and peptic ulcer disease, which are caused or mediated by Campylobacter pyloridis.
The use of Claim 7 wherein said medicament is prepared in oral form for the prevention of an infectious gastrointestinal disorder of the esophagus, stomach or duodenum.
The use of claim 7 or 8 wherein said manufacture comprises preparing of a medicament containing from 1 to 600 mg of nitrofurantoin in one or more unitary doses.
The use of claim 9 wherein said dose comprises from 1 to 200 mg of nitrofurantoin.